There is an urgent, unmet need for novel therapeutic approaches that are efficacious against lung cancer. Ranking first among cancer deaths in the U.S., this disease has 5-year relative survival rates of <20%. Most lung cancers are non-small cell (NSCLC, 85% of cases). Curative surgery is not an option for the 80% of NSCLC patients who present with advanced stage III cancer. For these patients chemo/radiation therapy remains the standard of care, and presently there is no effective strategy to improve radiation therapy outcomes. The central innovative theme of the proposed research is: a newly identified chemical entity YTR107 sensitizes human tumor cells to the lethal effects of ionizing radiation. YTR107 is efficacious in genetically diverse tumor types because its novel intracellular target plays a key role in homologous recombination, a critical DNA repair pathway utilized by dividing cells, including proliferative tumor cells. Targeting a key component of the DNA damage response pathway used by proliferating tumor cells (not quiescent differentiated cells) is a promising, novel therapeutic approach for NSCLCs. Genetic changes in these tumors result in high levels of replication stress and endogenous DNA damage. Constant replication stress renders tumor cells less competent to cope with additional exogenous DNA damage inflicted by therapeutic ionizing radiation. Radiation therapy combined with YTR107 may be ideally used on NSCLCs because ionizing radiation inflicts potentially lethal DNA double strand breaks and because YTR107 interferes with repair of these breaks by interfering with homologous recombination. Our ultimate product is an intravenous formulation of YTR107 used in combination with patients' radiotherapy regimens to effectively control primary tumor growth without promoting normal tissue damage. This outcome is paramount for preserving lung function and decreasing both cachexia severity and the probability of metastatic disease. Phase I goals for this collaborative research program at Cumberland Pharmaceuticals and Vanderbilt University are to: (1) demonstrate that YTR107 is an efficacious radiosensitizing agent in preclinical models of human NSCLC and (2) evaluate normal tissue toxicity by assessing whether YTR107 increases susceptibility to radiation-induced pulmonary fibrosis. YTR107 will change the standard of care for radiotherapy patients and improve therapeutic outcomes for intractable lung cancers, namely improved tumor response to irradiation with minimal drug effects on normal tissues.